The present invention relates to group A steptogramin derivatives of general formula: 
in which
R1 is a radical xe2x80x94NRxe2x80x2Rxe2x80x3 for which Rxe2x80x2 is a hydrogen atom or a methyl radical, and Rxe2x80x3 is a hydrogen atom or an alkyl, cycloalkyl, allyl, propynyl, benzyl or xe2x80x94ORxe2x80x2xe2x80x3 radical, Rxe2x80x2xe2x80x3 being a hydrogen atom or an alkyl, cycloalkyl, allyl, propynyl or benzyl radical, or Rxe2x80x3 represents xe2x80x94NR3R4, it being possible for R3 and R4 to represent a methyl radical, or to form together with the nitrogen atom to which they are attached a saturated or unsaturated 4- or 5-membered heterocycle which may, in addition, contain another heteroatom chosen from nitrogen, oxygen or sulphur,
R2 is a hydrogen atom or a methyl or ethyl radical, and
the bond  represents a single bond or a double bond,
as well as their salts, which exhibit a particularly advantageous antibacterial activity and a good degree of metabolic stability.
Among the known streptogramins, pristinamycin (RP 7293), an antibacterial of natural origin produced by Streptomyces pristinaespiralis was first isolated in 1955. The pristinamycin marketed under the name Pyrostacine7 consists mainly of pristinamycin IIA combined with pristinamycin IA.
Another antibacterial of the class of streptogramins: virginiamycin, has been prepared from Streptomyces virginiae, ATCC 13161 [Antibiotics and Chemotherapy, 5; 632 (1955)]. Virginiamycin (Staphylomycine7) consists mainly of factor M1 combined with factor S.
Semisynthetic derivatives of streptogramins of structure: 
for which n is 0 to 2 have been described in patents EP 135410 and EP 191662. Combined with a semisynthetic component of group B streptogramins they manifest a synergistic action and can be used by the injection route.
In general formula (I), unless otherwise stated, the alkyl radicals are straight or branched and contain 1 to 6 carbon atoms; the cycloalkyl radicals contain 3 to 4 carbon atoms; the chain  at the 16-position means: when Rxe2x80x3 is other than xe2x80x94ORxe2x80x2xe2x80x3 or xe2x80x94NR3R4, the R epimer or mixtures of the R and S epimers in which the R epimer is predominant, and when Rxe2x80x3 is xe2x80x94ORxe2x80x2xe2x80x3 or xe2x80x94NR3R4, the R and S epimers and mixtures thereof.
When Rxe2x80x3 is a radical xe2x80x94NR3R4 for which R3 and R4 form together with the nitrogen atom to which they are attached a saturated or unsaturated 4- or 5-membered heterocycle, the latter may be in particular azetidine, azolidine or imidazolyl.
The streptogramin derivatives of general formula (I) may be prepared from the components of the natural pristinamycin of general formula: 
in which R2 is as defined above, by the action of an amine of general formula:
H2Nxe2x80x94Rxe2x80x3xe2x80x83xe2x80x83(III)
in which Rxe2x80x3 is as defined above, followed by the action of an agent for reducing the intermediate enamine (or oxime) obtained, and then, when it is desired to obtain a streptogramin derivative of general formula (I) for which Rxe2x80x2 is a methyl radical, followed by a second reductive amination, by the action of formaldehyde or of a derivative generating formaldehyde in situ and the reduction of the intermediate enamine.
The action of the amine is generally carried out in an organic solvent such as an alcohol (for example methanol or ethanol), a chlorinated solvent (for example dichloromethane, dichloroethane or chloroform), a nitrile (for example acetonitrile), or pyridine, at a temperature of between 0 and 30 EC, and optionally in the presence of a dehydrating agent such as, for example, magnesium sulphate, sodium sulphate or molecular sieves. Preferably, the procedure is carried out under an inert atmosphere (for example argon). It is also possible to cause the amine salt to react. Preferably, to prepare derivatives for which the bond  represents a double bond, the procedure is carried out in an organic solvent such as a nitrile (for example acetonitrile) in the presence of an acid, such as an organic acid (for example acetic acid); in this case, the addition of a dehydrating agent is not necessary. When a streptogramin derivative of general formula (I) for which Rxe2x80x3 is a radical xe2x80x94ORxe2x80x2xe2x80x3 is prepared, it is possible to isolate the intermediate oxime of general formula: 
in which R2 and Rxe2x80x2xe2x80x3 are as defined above, and then to reduce this product to a derivative of general formula (I) for which Rxe2x80x2 is a hydrogen atom, and optionally use it in the subsequent reductive amination operation.
The reduction is carried out by the action of a reducing agent, for example an alkali metal borohydride (for example sodium cyanoborohydride or triacetoxyborohydride) in the presence of an organic acid (for example acetic acid) in an organic solvent as mentioned above for the amination reaction.
Where appropriate, the subsequent reductive amination operation, intended to obtain the disubstituted amine, is carried out under similar conditions.
According to the invention, the streptogramin derivatives of general formula (I) may also be prepared by the action of the ketone corresponding to the desired Rxe2x80x3 radical on the amine-containing derivative of general formula: 
in which R2 is as defined above, followed, when it is desired to obtain a streptogramin derivative of general formula (I) for which Rxe2x80x2 is a methyl radical, by a second reductive amination, by the action of formaldehyde or of a derivative generating formaldehyde in situ and the reduction of the intermediate enamine.
The reaction is carried out under conditions similar to those described above.
The amine of general formula (I) may be prepared as described above, from a streptogramin derivative of general formula (II).
The pristinamycin derivatives of general formula (II) correspond respectively-to pristinamycin IIA (PIIA), to pristinamycin IIB (PIIB), to pristinamycin IIC (PIIC), to pristinamycin IID (PIID), to pristinamycin IIF (PIIF), and to pristinamycin IIG (PIIG), which are known components of natural pristinamycin. The components PIIF and PIIG have been described in European patent application EP 614910.
Pristinamycin IIC (PIIC) and pristinamycin IID (PIID) may be obtained as described by J. C. Barrixc3xa8re et al., Expert. Opin. Invest. Drugs, 3(2), 115-31 (1994).
The preparation and separation of the components of the natural group A streptogramins [streptogramins of general formula (II)] is carried out by fermentation and isolation of the constituents from the fermentation broth according to or by analogy with the method described by J. Preud""homme et al., Bull. Soc. Chim. Fr., vol. 2, 585 (1968).
Alternatively, the preparation of the natural components of group A may be carried out by specific fermentation, as described in patent application FR 2,689,518.
The streptogramin derivatives of general formula (I) may be purified, where appropriate, by physical methods such as crystallization or chromatography.
The derivatives of general formula (I) may in particular be obtained in the form of the 16R epimer. The separation of the 16R epimer form and the 16S epimer form may be carried out by flash chromatography, by high-performance liquid chromatography (HPLC) or by centrifugal partition chromatography (CPC), from the mixture of the 16R and 16S epimers.
The streptogramin derivatives of general formula (I) may be converted to the state of addition salts with acids, by known methods. It is understood that these salts are also included within the scope of the present invention.
As examples of addition salts with pharmaceutically acceptable acids, there may be mentioned the salts formed with inorganic acids (hydrochlorides, hydrobromides, sulphates, nitrates, sulphates) or with organic acids (succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulphonates, ethanesulphonates, phenylsulphonates, p-toluenesulphonates, isethionates, naphthylsulphonates or camphorsulphonates, or with the substitution derivatives of these compounds).
The streptogramin derivatives according to the present invention have antibacterial properties and properties synergizing the antibacterial activity of the group B streptogramin derivatives. They are particularly advantageous because of their activity, alone or combined, as well as because of their enhanced metabolic stability compared with the previously known group A derivatives.
When they are combined with a component or a derivative of the group B streptogramins, they may be chosen, depending on whether it is desired to obtain an orally or parenterally administrable form, from the natural components: pristinamycin IA, pristinamycin IB, pristinamycin IC, pristinamycin ID, pristinamycin IE, pristinamycin IF, pristinamycin IG, virginiamycin S1, S3 or S4, vernamycin B or C, etamycin or from the semisynthetic derivatives as described in patents or patent applications U.S. Pat. Nos. 4,618,599, 4,798,827, 5,326,782, EP 772630 or EP 770132, in particular the streptogramin derivatives of general formula: 
in which,
1. Rb, Rc, Re and Rf are hydrogen atoms, Rd is a hydrogen atom or a dimethylamino radical, and Ra is a radical of structure xe2x80x94CH2Rxe2x80x2a for which Rxe2x80x2a is 3-pyrrolidinylthio or 3- or 4-piperidylthio which may be substituted with alkyl, or alkylthio substituted with 1 or 2 hydroxysulphonyl, alkylamino, dialkylamino (itself optionally substituted with mercapto or dialkylamino), or substituted with 1 or 2 optionally substituted piperazine rings, morpholino, thiomorpholino, piperidino, 1-pyrrolidinyl, 2-, 3- or 4-piperidyl or 2- or 3-pyrrolidinyl (which may be substituted with alkyl), or alternatively Ra is a radical of structure xe2x95x90CHRxe2x80x2a for which Rxe2x80x2a is 3-pyrrolidinylamino, 3- or 4-piperidylamino, 3-pyrrolidinyloxy, 3- or 4-piperidyloxy, 3-pyrrolidinylthio, 3- or 4-piperidylthio which may be substituted with alkyl, or Rxe2x80x2a is alkylamino, alkyloxy or alkylthio substituted with 1 or 2 hydroxysulphonyl, alkylamino, dialkylamino (itself optionally substituted with dialkylamino), or with trialkylammonio, 4- or 5-imidazolyl, or with 1 or 2 optionally substituted piperazine rings, morpholino, thiomorpholino, piperidino, 1-pyrrolidinyl, 2-, 3- or 4-piperidyl or 2- or 3-pyrrolidinyl (which may be substituted with alkyl), or Ra is a 3- or 4-quinuclidinylthiomethyl radical, or alternatively
2. Ra is a hydrogen atom and
a) either Rb, Re and Rf are hydrogen atoms, Rd is a radical xe2x80x94NHCH3 or xe2x80x94N(CH3)2 and Rc is a chlorine or bromine atom, or represents an alkenyl radical containing 3 to 5 carbon atoms [if Rd is xe2x80x94N(CH3)2],
b) or Rb, Rd, Re and Rf represent a hydrogen atom and Rc is a halogen, or an aminomonoalkyl, aminodialkyl, alkyloxy, trifluoromethoxy, thioalkyl, C1 to C3 alkyl or trihalomethyl radical,
c) or Rb, Rc, Re and Rf represent a hydrogen atom and Rd is a halogen, or an ethylamino, diethylamino or methylethylamino, alkyloxy or trifluoromethyloxy, thioalkyl, C1 to C6 alkyl, aryl or trihalomethyl radical,
d) or Rb, Re and Rf represent a hydrogen atom and Rc is halogen or an aminomonoalkyl or aminodialkyl, alkyloxy or trifluoromethyloxy, thioalkyl or C1 to C3 alkyl radical, and Rd is halogen or an amino, aminomonoalkyl or aminodialkyl, alkyloxy or trifluoromethyloxy, thioalkyl, C1 to C6 alkyl or trihalomethyl radical,
e) or Rc, Re and Rf represent a hydrogen atom and Rb and Rd represent a methyl radical.
It is understood that the combinations of the derivatives according to the invention and of the group B streptogramins are also included within the scope of the present invention.
In vivo, on experimental infections of mice with Staphylococcus aureus IP 8203 at doses of between 25 and 150 mg/kg orally and/or subcutaneously (CD50), they synergize the antimicrobial activity of pristinamycin IB of prostinamycin IA or of quinupristin (30/70 combination).
Finally, the products according to the invention are particularly advantageous because of their low toxicity. None of the products exhibited toxicity at doses of 300 mg/kg or greater than 300 mg/kg by the subcutaneous route.
Of particular interest are the products of general formula (I) for which R1 is a radical xe2x80x94NRxe2x80x2Rxe2x80x3 for which Rxe2x80x2 is a hydrogen atom or a methyl radical, and Rxe2x80x3 is a hydrogen atom, an alkyl, cycloalkyl, allyl, propynyl, benzyl or xe2x80x94ORxe2x80x2xe2x80x3 radical, Rxe2x80x2xe2x80x3 being an alkyl radical containing 1 to 6 carbon atoms, an allyl or propynyl radical, or Rxe2x80x3 represents xe2x80x94NR3R4, it being possible for R3 and R4 to represent a methyl radical, or to form together with the nitrogen atom to which they are attached a saturated or unsaturated 4- or 5-membered heterocycle which may, in addition, contain another heteroatom chosen from nitrogen, oxygen or sulphur, R2 is a hydrogen atom or a methyl or ethyl radical, and the bond  represents a single bond or a double bond, as well as their salts and in which the chain  at the 16-position means: when Rxe2x80x3 is other than xe2x80x94ORxe2x80x2xe2x80x3 or xe2x80x94NR3R4, the R epimer or mixtures of the R and S epimers in which the R epimer is predominant, and when Rxe2x80x3 is xe2x80x94ORxe2x80x2xe2x80x3 or xe2x80x94NR3R4, the R and S epimers and mixtures thereof; and among these products, most particularly the derivatives of general formula (I) for which R1 is a radical xe2x80x94NRxe2x80x2Rxe2x80x3 for which Rxe2x80x2 is a hydrogen atom or a methyl radical, and Rxe2x80x3 is a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms, a cycloalkyl, allyl, propynyl, benzyl or xe2x80x94ORxe2x80x2xe2x80x3 radical, Rxe2x80x2xe2x80x3 being an alkyl radical containing 1 to 3 carbon atoms, or an allyl or propynyl radical, or Rxe2x80x3 represents xe2x80x94NR3R4, it being possible for R3 and R4 to form together with the nitrogen atom to which they are attached a 5-membered saturated heterocycle, R2 is a methyl or ethyl radical, and the bond  represents a single bond or a double bond, as well as their salts and in which the chain  at the 16-position is as defined above.
More especially, among these products, the following derivatives are of great interest:
(16R)-16-dimethylamino-16-deoxopristinamycin IIA;
(16R)-16-methoxyamino-16-deoxopristinamycin IIB;
(16R)-16-ethoxyamino-16-deoxopristinamycin IIB;
(16R)-16-allyloxyamino-16-deoxopristinamycin IIB;.
(16R)-16-methoxyamino-16-deoxopristinamycin IIA.
The following examples, given with no limitation being applied, illustrate the present invention.
In the examples which follow, the 16-deoxopristinamycin IIA (or IIB) nomenclature means the replacement of the ketone function at the 16-position with 2 hydrogen atoms.